Benign Prostatic Hyperplasia (BPH) is a disease mainly occurring in elder males aged 50 years or above and accompanying urinary disorders, and its incidence rate increases with the age. The number of patients with BPH in Japan has been constantly increasing in recent years with the rapid aging of the population. BPH remarkably deteriorates the quality of life of the aged males due to urinary disorders, and it is an important disease in terms of medical economics since it is the most frequently diagnosed and treated disease in the medical field of urology.
It has been found that two factors, that is, direct urethral compression due to hypertrophy of the prostate (mechanical obstruction) and elevation of intraurethral pressure due to overcontraction of the prostatic smooth muscle via the sympathetic nerve (functional obstruction), are simultaneously involved in urinary disorders accompanying BPH. Drug therapy can deal with both of these mechanisms, and 5α-reductase inhibitors are mainly used for the mechanical obstruction and α1-sympatholytic agents (α1 blockers) are mainly used for the functional obstruction. 5α reductase inhibitors regress the prostate due to their anti-androgenic effect based on the suppression of the conversion of testosterone to 5α-dehydrotestosterone (DHT) which is a more potent androgen produced by a 5α-reductase. Only the prostatic epithelium regresses, however, and it takes a long period of time (several weeks to several months) for the drug efficacy to become apparent. On the other hand, since α1-blockers exert their drug efficacy swiftly after administration and are excellent in safety, α1-blockers are now the first-line agent for treating BPH. However, as a result of the long-term clinical studies, since a 5α-reductase inhibitor significantly delayed the transfer to invasive therapy as compared with the single use of an α1-blocker, and the like (“The New England Journal of Medicine”, 2003, Vol. 349, p. 2387-2398), the usefulness of 5α-reductase inhibitors has recently been recognized again.
It has been considered that DHT in the prostate is produced by 5α-reductase from testosterone, which is produced in the testes and secreted endocrinologically to the prostate. It has been reported recently, however, that about half of DHT and its precursor, testosterone, in prostate, are synthesized from dehydroepiandrosterone (DHEA), a steroid derived from an adrenal, in cells of the prostate (“Frontier in Neuroendocrinology”, 2001, Vol. 22, p. 185-212). This kind of sex hormone production system in the cells of the sex hormone target organs is called intracrinology.
It is difficult for 5α-reductase inhibitors to inhibit the local testosterone synthesis (intracrine testosterone synthesis) in the prostate. For example, it has been reported that the concentration of DHT in the prostate of the patients with BPH was decreased after the administration of finasteride, a 5α-reductase inhibitor, to about 20% of the concentration before the administration, while the concentration of testosterone, a precursor, in the prostate was inversely increased 4-fold (“The Journal of Urology”, 1999, Vol. 161, p. 332-337). It means that although the 5α-reductase inhibitor has an effect of reducing DHT concentration in the prostate, it has no effect of reducing the concentration of testosterone in the prostate and instead elevates the concentration. Since testosterone has an androgen receptor binding activity of about the half of that of DHT, this local elevation of the concentrations of testosterone in the prostate is considered to be partly responsible for insufficient drug efficacy of finasteride for BPH.
Anti-androgen therapies using surgical castration and gonadotropin releasing hormone agonists are also used for prostate cancer. These anti-androgen therapies have been reported to exert an insufficient effect of reducing the concentrations of testosterone in the prostate. For example, in patients with prostate cancer who receive the anti-androgen therapy, the concentration of testosterone in the blood decreased to about 10% of the concentration before the therapy, while the concentration of DHT in the prostate remained at about 50% (“The Journal of Clinical Endocrinology and Metabolism”, 1995, Vol. 80, p. 1066-1071). It suggests that the concentration of testosterone in the prostate is also not sufficiently reduced. Further, androgen receptors were localized in nuclei also in a prostate cancer recurring after anti-androgen therapy (Hormone Refractory Prostate Cancer), and no significant difference was observed between the concentration of testosterone in recurrent prostate cancer tissues and that in the normal prostate (“Clinical Cancer Research”, 2004, Vol. 10, p. 440-448). These reports strongly suggest that the effect of reducing the concentrations of testosterone in the prostate in existing therapeutic methods is quite insufficient for treating recurrent prostate cancer and that suppression of the testosterone synthesizing mechanism in the prostate, that is, intracrine testosterone synthesis in the prostate may be a new target of prostate cancer therapy.
Based on the known arts described above, since inhibitors of intracrine testosterone synthesis in the prostate have an effect of reducing the concentrations of testosterone in the prostate and no effect of reducing the concentrations of testosterone in the blood, the inhibitors are expected to be very attractive agent for treating BPH and/or an agent for treating prostate cancer, (1) which can reduce not only the concentration of testosterone but also the concentration of DHT in the prostate and (2) which can avoid the adverse effects due to the suppression of the concentration of the testosterone derived from testes in the blood.
17β-hydroxysteroid dehydrogenase (17βHSD) is essential for the biosynthesis of testosterone. There are several subtypes of 17βHSD. 17βHSD type 5 is highly expressed in a human prostate and increases of the expression were reported for prostate cancer and recurrent prostate cancer (“Steroids”, 2004, Vol. 69, p. 795-801; and “Cancer Research”, 2006, Vol. 66, p. 2815-2825). On the other hand, almost all the testosterone in the blood is produced by 17βHSD type 3 in testes and the expression of 17βHSD type 3 is rarely observed in other tissues including the prostate (“Nature Genetics”, 1994, Vol. 7, p. 34-39). 17βHSD type 5 is thus considered to be responsible for the intracrine testosterone synthesis in the prostate and selective inhibitors of 17βHSD type 5 are expected to suppress intracrine testosterone synthesis in the prostate selectively. Further, since the contribution of 17βHSD type 5 has been pointed out also in estrogen-dependent tissues such as the mammary gland and the like, the selective inhibitors are expected to be effective for estrogen-dependent diseases such as breast cancer and the like (“Endocrine Reviews”, 2003, Vol. 24, p. 152-182). In addition, it is reported that AKR1C3 (another name for 17βHSD type 5), which is a subtype of aldo-keto reductase (AKR), metabolizes Polycyclic Aromatic Hydrocarbon (PAH) to generate reactive oxygen species (ROS) (“The Journal of Biological Chemistry”, 2002, Vol. 277, No. 27, p. 24799-24808) and that single nucleotide polymorphism (SNP) of AKR1C3 gene relating to oxidative stress correlates with a risk of lung cancer (“Carcinogenesis”, 2004, Vol. 25, No. 11, p. 2177-2181). That is, it is suggested that the activity of AKR1C3 in the lungs increases the risk of lung cancer via generation of ROS from PAH and selective inhibitors of 17βHSD type 5 are expected to be effective for lung cancer.
As 17βHSD type 5 inhibitors, steroid derivatives (Patent Document 1) and NSAIDs (Non-steroidal Anti-Inflammatory Drugs) such as flufenamic acid, indomethacin and the like (Non-Patent Document 1), cinnamic acid derivatives (Non-Patent Document 2) and the like have been reported. Although the mechanism of action is different, an indazole derivative containing a compound of formula (A) is known to be effective for BPH (Patent Document 2).

Patent Document 3 discloses that N-substituted benzimidazole derivatives including a compound of formula (B) have an inhibitory action against the c-Kit oncogene and are useful for prostate cancer or the like. However, there is no disclosure of an indolyl group, and there is also no description of an inhibitory action against 17βHSD type 5.

Patent Document 4 discloses that benzimidazole derivatives including a compound of formula (C) have a tyrosine kinase regulatory action and are useful for prostate cancer or the like. However, there is no disclosure of an indolyl group, and there is also no description of an inhibitory action against 17βHSD type 5.

Patent Document 5 discloses that indole derivatives including a compound of formula (D) have a histamine H4 antagonistic action, and are useful for inflammation. However, there is no disclosure of a non-basic (piperidyl) alkanol structure, and there is also no description of an inhibitory action against 17βHSD type 5, and effectiveness for BPH, prostate cancer and the like.

Patent Document 6 discloses that indole derivatives including a compound of formula (E) have a cannabinoid receptor regulatory action, and are useful for cerebrovascular disorders and the like. However, there is also no description of an inhibitory action against 17βHSD type 5, and effectiveness for BPH, prostate cancer and the like.

[Patent Document 1] Pamphlet of International Publication No. WO99/046279
[Patent Document 2] Pamphlet of International Publication No. WO2004/064735
[Patent Document 3] Pamphlet of International Publication No. WO2005/021531
[Patent Document 4] Pamphlet of International Publication No. WO2007/056155
[Patent Document 5] Pamphlet of International Publication No. WO2002/072548
[Patent Document 6] JP-A-2005-162657
[Non-Patent Document 1] Cancer Research, 2004, Vol. 64, p. 1802-1810
[Non-Patent Document 2] Molecular and Cellular Endocrinology, 2006, Vol. 248, p. 233-235